Compositions and methods for treatment of disorders or conditions of the eye

ABSTRACT

The invention provides compositions comprising low concentrations of selective α-2 adrenergic receptor agonists in combination with potassium and/or calcium. Methods for treating eye disorders and conditions are also provided. The compositions preferably comprise brimonidine.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 12/460,942, filed Jul. 27, 2009, which claims a priority ofU.S. Provisional Application Ser. Nos. 61/137,714, filed on Aug. 1,2008; 61/192,777, filed on Sep. 22, 2008; 61/203,120, filed on Dec. 18,2008; and 61/207,481 filed on Feb. 12, 2009. This application alsoclaims a priority of U.S. Provisional Application Ser. No. 61/287,548,filed on Dec. 17, 2009. The contents of the above-mentioned applicationsare hereby incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

A variety of diseases and conditions can cause reddening of an eye,including, but not limited to such conditions as dry eye, contact lenswear, allergic conjunctivitis, glaucoma, topical glaucoma medications,idiopathic, smoking, alcohol abuse, drug use, lack of sleep, allergicrhinitis, nonallergic rhinitis, and acute or chronic sinusitis.

In addition, healthy individuals may have natural off white or slightlyyellow shading of their sclera and or episclera. A normal healthy eyehas a certain baseline level of whiteness, which slightly varies fromperson to person. Whiter eyes are traditionally a societal symbol ofnatural healthy eyes, and excellent overall hygiene and health. Thus, itmay be desirable to increase whiteness of an eye several shades beyondthe baseline of a particular eye, even when the eye and/or theindividual is healthy to project an image of health, attractiveness, orother related benefit. This increase in whiteness may be important forcosmetic or other reasons.

A human eye has a lot of α-2 adrenergic receptors. Selective agonists ofthese receptors (i.e., compounds which preferentially bind to α-2adrenergic receptors) at sufficiently low concentrations may have aneffect on an eye's appearance by causing lumen size reduction of α-2receptor populated arterioles and, particularly, terminal arterioles andpostcapillary venules. This may result in vasoconstriction, and moreparticularly, microvessel lumen size reduction, which in turn mayincrease the per unit surface area degree of microvessel constriction,and therefore, improve cosmetic appearance of eyes with insignificant tominimal reduction of larger vessels thereby preventing ischemia.

It would be desirable to enhance the vasoconstrictive activity of α-2adrenergic receptor agonists and/or further reduce undesirablehyperemia. Accordingly, there is a need for new compositions and methodsthat would enhance the vasoconstrictive activity of α-2 adrenergicreceptor agonists.

SUMMARY OF THE PRESENT INVENTION

The present invention provides compositions comprising lowconcentrations of selective α-2 adrenergic receptor agonists incombination with potassium and/or calcium.

In preferred embodiments, the compositions are used for treatment of eyedisorders or conditions.

In one embodiment, low concentrations of selective α-2 adrenergicreceptor agonists, in combination with potassium and/or calcium, allowsignificant improvement in tissue hemodynamics.

In one embodiment, the invention provides a composition for use intreatment of eye disorders or conditions, wherein said compositioncomprises a selective α-2 adrenergic receptor agonist having a bindingaffinity of 100 fold or greater for α-2 over α-1 adrenergic receptors,or a pharmaceutically acceptable salt thereof, wherein said α-2adrenergic receptor is present at a concentration from between about0.001% to about 0.05% weight by volume of the composition, and whereinsaid composition comprises potassium and/or calcium.

In preferred embodiments, potassium is in the form of potassiumchloride, and calcium is in the form of calcium chloride.

In even more preferred embodiments, the concentration of potassiumchloride is between about 5 mM to about 100 mM; in more preferredembodiments between about 10 mM to about 70 mM; and in even morepreferred embodiments between about 10 mM to about 50 mM; and theconcentration of calcium chloride is between about 0.05 mM to about 5mM; and in even more preferred embodiments between about 1 mM to about 2mM.

Selective α-2 adrenergic receptor agonists include, but are not limitedto, lofexidine, apraclonidine, mivazerol, clonidine, brimonidine, alphamethyl dopa, guanfacine, dexmedetomidine,(+)-(S)-4-[1-(2,3-dimethyl-phenyl)-ethyl]-1,3-dihydro-imidazole-2-thione,1-[(imidazolidin-2-yl)imino]indazole, and mixtures of these compounds.

In a preferred embodiment, the invention provides a composition for usein treatment of eye disorders or conditions, wherein said compositioncomprises between about 0.001% to about 0.05% weight by volume ofbrimonidine, between about 0.2% to about 0.3% weight by volume of boricacid, between about 10 mM to about 70 mM of potassium chloride, betweenabout 0.05 mM and about 2 mM of calcium chloride, wherein pH of saidcomposition is between about 5.5 and about 7.5, and wherein osmolalityof said composition is between about 250 mOsm/kg and about 300 mOsM/kg.

In some embodiments, the compositions of the invention comprisehypromellose.

In some embodiments, the invention provides methods of treatment of eyedisorders or conditions, comprising administering to an eye of a patientin need thereof a composition, wherein said composition comprises aselective α-2 adrenergic receptor agonist having a binding affinity of100 fold or greater for α-2 over α-1 adrenergic receptors, or apharmaceutically acceptable salt thereof, wherein said α-2 adrenergicreceptor is present at a concentration from between about 0.001% toabout 0.05% weight by volume of the composition, and wherein saidcomposition comprises potassium and/or calcium.

The invention also provides methods of enhancing vasoconstrictingactivity of a selective α-2 adrenergic receptor agonist having a bindingaffinity of 100 fold or greater for α-2 over α-1 adrenergic receptorscomprising adding potassium and/or calcium to a pharmaceuticalcomposition which comprises said selective α-2 adrenergic receptoragonist.

Eye disorders and conditions include both therapeutic and cosmeticconditions. For example, one might wish to cause an eye whitening eitherfor cosmetic reasons or to reverse an eye reddening effect of variousdiseases and conditions. These diseases and conditions may be ocular,pulmonary or others, and include, but are not limited to, dry eye,contact lens wear, allergic conjunctivitis, allergic rhinitis,nonallergic rhinitis, acute or chronic sinusitis, nasal polyposis,rhinitis secondary to pregnancy, rhinitis due to nasal septal deviationor obstruction, asthma, particularly, allergic asthma and others.

DETAILED DESCRIPTION OF THE INVENTION Definitions

For purposes of the present invention, the terms below are defined asfollows.

The term “selective α-2 adrenergic receptor agonists” encompasses allα-2 adrenergic receptor agonists which have a binding affinity of 100fold or greater for α-2 over α-1 adrenergic receptors. The term alsoencompasses pharmaceutically acceptable salts, esters, prodrugs, andother derivatives of selective α-2 adrenergic receptor agonists.

The term “low concentrations” refers to concentrations from betweenabout 0.0001% to about 0.05%; more preferably, from about 0.001% toabout 0.05%; even more preferably, from about 0.01% to about 0.025%; andeven more preferably, from about 0.01% to about 0.02% weight by volumeof the composition. Preferably, the concentrations of the selective α-2adrenergic receptor agonists are substantially lower than theconcentrations normally used in the treatment of glaucoma. The term“substantially” refers to such concentration that would not previouslybe considered effective for the treatment of glaucoma.

The term “brimonidine” encompasses, without limitation, brimonidinesalts and other derivatives, and specifically includes, but is notlimited to, brimonidine tartrate,5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline D-tartrate, Alphagan™, andUK14304.

The term “potassium” encompasses potassium salts and specificallyincludes, but is not limited to, potassium chloride.

The term “calcium” encompasses calcium salts and specifically includes,but is not limited to, calcium chloride.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, from acombination of the specified ingredients in the specified amounts.

The terms “treating” and “treatment” refer to reversing, alleviating,inhibiting, or slowing the progress of the disease, disorder, orcondition to which such terms apply, or one or more symptoms of suchdisease, disorder, or condition.

The terms “preventing” and “prevention” refer to prophylactic use toreduce the likelihood of a disease, disorder, or condition to which suchterm applies, or one or more symptoms of such disease, disorder, orcondition. It is not necessary to achieve a 100% likelihood ofprevention; it is sufficient to achieve at least a partial effect ofreducing the risk of acquiring such disease, disorder, or condition.

Embodiments of the Invention

In accordance with the invention, selective alpha-2 (α-2) adrenergicreceptor agonists (which are interchangeably referred to as “α-2agonists” throughout the application) at sufficiently lowconcentrations, in combination with potassium alone and/or potassium andcalcium together, allow significant improvement in tissue hemodynamicsand can be used for treatment of eye disorders or conditions.

The selective α-2 agonists at low concentrations promotevasoconstriction and allow reducing, minimizing, and/or eliminatinghyperemia, including rebound hyperemia while optimally providingclinically equal or more effective vasoconstriction. While not wishingto be bound to any particular theory, it is believed that reboundhyperemia is primarily associated with α-1 agonist activity. Thus,unless the binding affinity of α-2 agonists for α-2 over α-1 adrenergicreceptors is sufficiently high, not sufficiently selective α-2 agonistswill cause undesirable α-1 receptor stimulation with attendant reboundhyperemia. Accordingly, it is desired to minimize α-1 agonist activityby using selective α-2 agonists.

Potassium and/or calcium are able to potentiate the effects of selectiveα-2 agonists. While not wishing to be bound to any specific theory, itis believed that potassium and calcium ions are able to create a minielectric current which can stimulate the constriction of the smoothmuscle of a vessel, provided intracellular calcium is present. In thepresence of α-2 agonists, even small amounts of potassium with orwithout exogenous calcium ions, even if not themselves sufficient forsuch voltage potential changes, may enhance α-2 agonists'vasoconstrictive activity, including onset, degree of vasoconstriction,and duration. Thus, potassium and/or calcium are believed to enhanceand/or improve vasoconstrictive effects of α-2 agonists.

Thus, in one embodiment, the present invention provides compositionscomprising low concentrations of selective α-2 adrenergic receptoragonists in combination with potassium alone and/or potassium andcalcium together.

In preferred embodiments, the compositions are used for treatment of eyedisorders or conditions.

In some embodiments, the invention provides methods of treatment of eyedisorders and conditions comprising administering to an eye of a patientin need thereof a composition, wherein said composition comprises lowconcentrations of selective α-2 agonists in combination with potassiumand/or potassium and calcium together, and in some cases, calcium alone.

In some embodiments, the methods and compositions of the invention maybe used to reduce eye reddening and/or achieve eye whitening by reducinghyperemia caused by a disease or a condition.

In other embodiments, the methods and compositions of the invention maybe used to achieve eye whitening in healthy eyes.

In some embodiments, the methods and compositions of the invention maybe used to both achieve cosmetic eye whitening and to reduce eyereddening due to a disease or a condition.

Although this application is focused on the eye, any α-2 agonistactivity may be enhanced by the addition of K and Ca. For example, α-2agonist activity in nasal decongestion, pulmonary uses, and/or otheruses of α-2 agonists such as described in U.S. patent application Ser.Nos. 12/460,942; 12/460,968; 12/460,941; 12/460,967; 12/460,970;12/460,954; 12/460,969; 61/287,533; and 61/287,518 may be enhanced andis intended to be covered here by this application. Further, forpulmonary use such enhancement is at sufficiently low dose of potassiumand calcium to facilitate α-2 agonist activity without causingbronchiole constriction.

Selective α-2 Adrenergic Receptor Agonists Suitable for the Purposes ofthe Invention

In some embodiments of the invention, selective α-2 adrenergic receptoragonists have binding affinities (K_(i)) for α-2 over α-1 receptors of100:1 or greater. In preferred embodiments of the invention, selectiveα-2 adrenergic receptor agonists have K_(i) for α-2 over α-1 receptorsof 500:1 or greater, more preferably 700:1 or greater, even morepreferably 1000:1 or greater, and most preferably, 1500:1 or greater.

The particularly preferred adrenergic receptor agonists for the purposesof the present invention have higher selectivity for α-2B and/or α-2Creceptors, as compared to α-2A receptors.

In preferred embodiments of the invention, concentrations of selectiveα-2 adrenergic receptor agonists are from between about 0.0001% to about0.05%; more preferably, from about 0.001% to about 0.05%; even morepreferably, from about 0.01% to about 0.025%; and even more preferably,from about 0.01% to about 0.02% weight by volume of the composition.

In principle, any selective α-2 adrenergic receptor agonist may besuitable for the purposes of the present invention. In one embodiment,the selective α-2 adrenergic receptor is selected from the groupconsisting of apraclonidine, mivazerol, clonidine, brimonidine, alphamethyl dopa, guanfacine, dexemeditomidine,(+)-(S)-4-[1-(2,3-dimethyl-phenyl)-ethyl]-1,3-dihydro-imidazole-2-thione,1-[(imidazolid in-2-yl)imino]indazole, and mixtures of these compounds.

The compositions and methods of the inventions encompass all isomericforms of the described α-2 adrenergic receptor agonists, their racemicmixtures, enol forms, solvated and unsolvated forms, analogs, prodrugs,derivatives, including but not limited to esters and ethers, andpharmaceutically acceptable salts, including acid addition salts.Examples of suitable acids for salt formation are hydrochloric,sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic,furmaric, succinic, ascorbic, maleic, methanesulfonic, tartaric, andother mineral carboxylic acids well known to those in the art. The saltsmay be prepared by contacting the free base form with a sufficientamount of the desired acid to produce a salt in the conventional manner.The free base forms may be regenerated by treating the salt with asuitable dilute aqueous base solution such as dilute aqueous hydroxidepotassium carbonate, ammonia, and sodium bicarbonate. The free baseforms differ from their respective salt forms somewhat in certainphysical properties, such as solubility in polar solvents, but the acidsalts are equivalent to their respective free base forms for purposes ofthe invention. (See, for example S. M. Berge, et al., “PharmaceuticalSalts,” J. Pharm. Sci., 66: 1-19 (1977) which is incorporated herein byreference).

As long as a particular isomer, salt, analog, prodrug or otherderivative of a selective α-2 adrenergic receptor agonist functions as aselective α-2 agonist, it may be used for the purposes of the presentinvention.

When choosing a particular α-2 adrenergic receptor agonist, one may takeinto account various considerations including blood brain permeabilityand any possible side effects and other systemic reactions.

In preferred embodiments of the invention, the selective α-2 adrenergicreceptor is brimonidine or its salt. In a more preferred embodiment, theselective α-2 adrenergic receptor agonist is the tartrate salt ofbrimonidine.

Compositions and Methods of the Invention

In one embodiment, the present invention provides compositionscomprising low concentrations of selective α-2 adrenergic receptoragonists in combination with potassium and/or calcium. In preferredembodiments, the compositions are used for treatment of eye disorders orconditions.

In one embodiment, the invention provides a composition for use intreatment of eye disorders or conditions, wherein said compositioncomprises a selective α-2 adrenergic receptor agonist having a bindingaffinity of 100 fold or greater for α-2 over α-1 adrenergic receptors,or a pharmaceutically acceptable salt thereof, wherein said α-2adrenergic receptor is present at a concentration from between about0.001% to about 0.05% weight by volume of the composition, wherein saidcomposition comprises potassium and/or calcium.

In preferred embodiments, potassium is in the form of potassiumchloride, and calcium is in the form of calcium chloride.

In even more preferred embodiments, the concentration of potassiumchloride is between about 5 mM to about 100 mM; more preferably betweenabout 10 mM to about 70 mM; and even more preferably between about 10 mMto about 50 mM, and most preferably about 40 mM; and the concentrationof calcium chloride is between about 0.05 mM to about 5 mM, morepreferably between about 0.05 mM to about 2 mM, and most preferablyabout 1 mM.

In one embodiment, a pH of the compositions of the present invention isless than about 8.0, preferably, between about 5.5 and about 8.0, morepreferably between about 5.5 and about 7.5, even more preferably betweenabout 6.0 and about 7.0, and most preferably about 6.5.

Preferably, osmolality of the compositions of the present invention isbetween about 250 mOsm/kg and about 300 mOsm/kg; most preferably, about270 mOsm/kg.

The compositions of the present invention are preferably formulated fora mammal, and more preferably, for a human.

In one embodiment, the invention provides a composition for inducingvasoconstriction consisting essentially of brimonidine and/or potassium,wherein said brimonidine concentration is from between about 0.01% toabout 0.02% weight by volume, wherein pH of said composition is betweenabout 5.5 and about 6.5, and wherein said composition is formulated asan ocular drop.

In another embodiment, the invention provides an aqueous composition fortreatment of eye disorders or conditions, comprising between about 0.01%to about 0.025% weight by volume of brimonidine and from between about0.1 to about 0.5% weight by volume of potassium chloride, wherein pH ofsaid composition is between about 7.0 and about 8.0, and wherein saidcomposition is formulated as an ocular drop.

In a preferred embodiment, the invention provides a composition for usein treatment of eye disorders or conditions, wherein said compositioncomprises between about 0.001% to about 0.05% weight by volume ofbrimonidine, between about 0.2% to about 0.3% weight by volume of boricacid, between about 10 mM to about 70 mM of potassium chloride, betweenabout 0.05 mM and about 2 mM of calcium chloride, wherein pH of saidcomposition is between about 6.0 and about 7.0, and wherein osmolalityof said composition is between about 250 mOsm/kg and about 300 mOsm/kg.

The compositions of the invention may also comprise a solubilitystabilizer which preferably contains an anionic component, such asperoxide class preservatives. The solubility stabilizer allows one toachieve greater penetration of lipophilic membranes. In a preferredembodiment, the solubility stabilizer comprises a stabilized oxychlorocomplex, chlorite, and sodium perborate.

The compositions of the present invention may comprise nitrous oxideinhibitors. In a preferred embodiment, the nitrous oxide inhibitors areselected from the group consisting of L-NAME (L-N^(G)-Nitroargininemethyl ester), L-NIL (N-6-(1-Iminoethyl)-L-lysine dihydrochloride),L-NIO (N-5-(1-Iminoethyl)-L-ornithine dihydrochloride), and L-canavine,or combinations thereof. Preferably, concentration of the nitrous oxideinhibitors is between about 0.005% and about 0.5% weight by volume.

In one embodiment of the invention, the compositions are delivered asophthalmic solutions into the eyes. The invention also contemplatestopical compositions which include, but are not limited to, gels andcreams. They may also include additional non-therapeutic components,which include, but are not limited to, preservatives, delivery vehicles,tonicity adjustors, buffers, pH adjustors, antioxidants, tenacityadjusting agents, viscosity adjusting agents, and water.

Preservatives include, but are not limited to, benzalkonium chloride,chlorobutanol, thimerosal, phenylmercuric acetate, or phenylmercuricnitrate.

Delivery vehicles include, but are not limited to, polyvinyl alcohol,povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethylcellulose, hydroxyethyl cellulose and purified water. It is alsopossible to use a physiological saline solution as a major vehicle.

Tonicity adjustors include, but are not limited to, a salt such assodium chloride, potassium chloride, mannitol or glycerin, or anotherpharmaceutically or ophthalmically acceptable tonicity adjustor.

Tenacity adjusting agents include, but are not limited to, glycerin.

Viscosity adjusting agents include, but are not limited to, hypromellose(HPMC).

Buffers and pH adjustors include, but are not limited to, acetatebuffers, citrate buffers, phosphate buffers and borate buffers, such asboric acid. It is understood that various acids or bases can be used toadjust the pH of the composition as needed. pH adjusting agents include,but are not limited to, sodium hydroxide and hydrochloric acid.

Antioxidants include, but are not limited to, sodium metabisulfite,sodium thiosulfate, acetylcysteine, butylated hydroxyanisole andbutylated hydroxytoluene.

To make the topical compositions of the present invention, one cansimply dilute, using methods known in the art, more concentratedsolutions of selective α-2 agonists. The precise method of carrying outthe dilutions is not critical. Any commonly used diluents, includingpreservatives described above in the application, suitable for topicalsolutions can be used.

In other embodiments, the compositions of the invention may beformulated and delivered as intravenous, oral, aerosolized, andnebulized compositions.

In some embodiments, the invention provides the following compositions:

-   -   brimonidine or its derivative at the following possible        concentrations (0.001%, 0.005%; 0.01%, 0.025% and 0.05%);    -   boric acid at concentration between about 0.2% and 0.3%;    -   a pH adjusting agent (e.g., NaOH and/or HCl);    -   a tenacity adjusting agent (e.g., glycerin) (possible osmolality        is between 240 and 270 mOsm/kg);    -   potassium chloride at about 0.15% (about 20 mM);    -   calcium chloride at about 0.06% (about 1 mM); and    -   optionally, HPMC at about 0.25%.

In some embodiments, the invention provides methods of treatment of eyedisorders and conditions comprising administering to an eye of a patientin need thereof a composition, wherein said composition comprises lowconcentrations of selective α-2 agonists in combination with potassiumand/or calcium.

In some embodiments, the methods and compositions of the invention maybe used to reduce eye reddening and/or achieve eye whitening by reducinghyperemia caused by a disease or a condition.

In other embodiments, the methods and compositions of the invention maybe used to achieve eye whitening in healthy eyes.

In some embodiments, the methods and compositions of the invention maybe used to both achieve cosmetic eye whitening and to reduce eyereddening due to a disease or a condition.

In some embodiments, the invention also provides methods of enhancingvasoconstricting activity of a selective α-2 adrenergic receptor agonisthaving a binding affinity of 100 fold or greater for α-2 over α-1adrenergic receptors comprising adding potassium and/or calcium to apharmaceutical composition which comprises said selective α-2 adrenergicreceptor agonist.

Eye disorders and conditions include, but are not limited to, red eye,including chronic red eye; ocular vascular congestion after Lasiksurgery; prophylactic intraoperative and postoperative reduction ofhemorrhage and hyperemia after Lasik surgery; preoperative hemorrhageand hyperemia prophylaxis prior to Lasik surgery; prophylactic diabeticretinopathy; macular edema such as that associated with diabetes;conditions of retinal degeneration such as glaucoma, maculardegeneration such as age-related macular degeneration (ARMD) andretinitis pigmentosa; retinal dystrophies; elevated baseline hyperemiain glaucoma patients; inflammatory disorders of the retina; vascularocclusive conditions of the retina such as retinal vein occlusions orbranch or central retinal artery occlusions; retinopathy of prematurity;retinopathy associated with blood disorders such as sickle cell anemia;elevated intraocular pressure; ocular itch; damage following retinaldetachment; damage or insult due to vitrectomy, retinal or othersurgery; and other retinal damage including therapeutic damage such asthat resulting from laser treatment of the retina, for example,pan-retinal photocoagulation for diabetic retinopathy or photodynamictherapy of the retina; generic and acquired optic neuropathies such asoptic neuropathies characterized primarily by loss of central vision,for example, Leber's hereditary optic neuropathy (LEON), autosomaldominant optic atrophy (Kjer disease) and other optic neuropathies suchas those involving mitochondrial defects aberrant dynamin-relatedproteins or inappropriate apoptosis; and optic neuritis such as thatassociated with multiple sclerosis, retinal vein occlusions orphotodynamic or laser therapy. See, for example, Carelli et al.,Neurochem. Intl. 40:573-584 (2002); and Olichon et al., J. Biol. Chem.278:7743-7746 (2003).

The term “eye disorders and conditions” also encompasses aestheticconditions, for example, excessive redness of an eye. The methods andcompositions of the present invention can be used with other ocularprocedures, particularly cataract surgery, retinal surgery, pterygiaeremoval, and motility surgery. At the concentration range employed toeliminate hyperemia, endothelial cell pump dysfunction, and the highlevel of allergic reactions of the glaucoma class of brimonidineconcentrations, no intraocular pressure effects are noted. This isimportant because in cosmetic use, while retention of normal intraocularpressure is desired, lowering of intraocular pressure is not a necessaryor desirable parameter to reduce in a normotensive population.

Dosages

Proper dosages of the compositions of the present invention areconcentration-dependent. To determine the specific dose for whitening ofeyes of a specific person, a skilled artisan would have to take intoaccount kinetics and absorption characteristics of the particularselective α-2 adrenergic receptor agonist. In addition, the dosage maybe dependent on the route of administration. The dosages may also dedependent on the type of a particular disorder and/or condition and alsoon the degree of whitening desired by a patient.

The following prophetic Example is provided solely for illustrativepurposes and is not meant to limit the invention in any way.

Example 1 Effect of Calcium and Potassium on Increasing Whiteness of anEye

The following experiment may be set up. To assess the effect of calciumand potassium on increasing the effectiveness of selective α-2 receptoragonists, one can compare the results of administrating a selective α-2receptor agonist with and without potassium and calcium.

For example, a patient who has redness in both eyes (whether pathologicor non-pathologic) may be treated as follows:

to the right eye, a composition may be administered comprising about0.025% weight by volume of brimonidine; and

to the left eye, a composition may be administered comprising about0.025% weight by volume of brimonidine; about 50 mM of potassiumchloride and about 1 mM of calcium chloride.

Assessments may be made, for example, 5 minutes after the administrationand 4 hours after the administration. In addition, the compositions maybe re-administered, for example, after the four hours assessment.

It is theoretically believed that the left eye of the patient will bewhitened and/or redness reduced significantly more as compared with theright eye.

1. A composition for use in treatment of eye disorders and conditions, wherein said composition comprises a selective α-2 adrenergic receptor agonist having a binding affinity of 100 fold or greater for α-2 over α-1 adrenergic receptors, or a pharmaceutically acceptable salt thereof, wherein said α-2 adrenergic receptor agonist is present at a concentration from between about 0.001% to about 0.05% weight by volume of the composition, and wherein said composition comprises potassium and/or calcium.
 2. The composition of claim 1, wherein said potassium is in the form of potassium chloride, wherein said potassium chloride is present at a concentration of about 10 mM to about 50 mM, wherein said calcium is in the form of calcium chloride, and wherein said calcium chloride is present at a concentration of about 0.05 mM to about 2 mM.
 3. A composition for use in treatment of eye disorders and conditions, wherein said composition comprises between about 0.001% to about 0.05% weight by volume of brimonidine, between about 0.2% to about 0.3% weight by volume of boric acid, between about 10 mM to about 70 mM of potassium chloride, between about 0.05 mM and about 2 mM of calcium chloride, wherein pH of said composition is between about 5.5 and about 7.5, and wherein osmolality of said composition is between about 250 mOsm/kg and about 300 mOsm/kg.
 4. A method of treating eye disorders or conditions comprising administering to an eye of a patient in need thereof an effective amount of the composition of claim
 1. 5. A method of enhancing vasoconstricting activity of a selective α-2 adrenergic receptor agonist comprising adding potassium and/or calcium to a pharmaceutical composition which comprises said selective α-2 adrenergic receptor agonist. 